Comparison of central nervous system prophylaxis with cranial radiation and intrathecal methotrexate versus intrathecal methotrexate alone in acute lymphoblastic leukemia

In acute lymphoblastic leukemia (ALL), central nervous system (CNS) prophylaxis with cranial irradiation plus 5 doses of intrathecal methotrexate (i.t. MTX) reduces the incidence of CNS relapse to 7%-15%. However, increased evidence of CNS delayed toxicity started to be recognized as CT scan abnormalities and neuropsychologic alterations, mainly in children. Two questions were analyzed in the present report: (1) Will further doses of i.t. methotrexate and dexamethasone (i.t. MTX- DMT) decrease the incidence of CNS relapse in patients treated early in remission with cranium irradiation plus i.t. MTX-DMT even more? (2) Is i.t. MTX-DMT given during induction and maintenance equally as effective as cranium irradiation plus i.t. MTX-DMT? A randomized study was designed to answer the first question. Incidence of primary CNS relapse in i.t. MTX-DMT-treated patients with a WBC count less than 50,000 was 11% (15 of 135 patients) and was 11% (17 of 150) in the untreated group. In patients with a WBC count greater than 50,000, it was 16% (6/37) in the treated group and 19% (6/31) in the control group. No difference was observed according to treatment in both prognostic groups. Patients in this study were retrospectively compared with a consecutive protocol in which patients received 3 doses of i.t. MTX-DMT alone during induction plus 3 doses weekly during the first month of remission and every 3 mo thereafter. The incidence of primary CNS leukemia at 60 mo in patients with a WBC count less than 50,000 was 20% in the irradiated group and 32% in the group with i.t. MTX-DMT alone. This difference was not significant. However, the relapse-free survival at 60 mo was 26% and 41%, respectively, (p less than 0.0005). The incidence of primary CNS relapse in patients with a WBC count more than 50,000 at 48 mo was 28% in the irradiated group and 42% in the nonirradiated group. The difference was not significant. The duration of complete remission was similar, remaining at 15% and 16% of patients disease-free at 48 mo, respectively. We conclude that (A) after cranial irradiation plus i.t. MTX-DMT X 5, the use of additional doses of i.t. MTX-DMT is not of further benefit in preventing CNS relapse; (B) the use of i.t. MTX-DMT alone compares similarly with cranial irradiation plus i.t. MTX-DMT in the incidence of CNS relapse; and (C) relapse-free survival and survival in patients with a WBC count less than 50,000 were significantly longer in those without cranial irradiation.

Download Full-text

Comparison of central nervous system prophylaxis with cranial radiation and intrathecal methotrexate versus intrathecal methotrexate alone in acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v62.2.241.241 ◽

1983 ◽

Vol 62 (2) ◽

pp. 241-250 ◽

Cited By ~ 24

Author(s):

FS Muriel ◽

E Svarch ◽

S Pavlovsky ◽

M Eppinger-Helft ◽

J Braier ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cranial Irradiation ◽

Intrathecal Methotrexate ◽

Relapse Free Survival ◽

Free Survival ◽

Cns Relapse ◽

Wbc Count

Abstract In acute lymphoblastic leukemia (ALL), central nervous system (CNS) prophylaxis with cranial irradiation plus 5 doses of intrathecal methotrexate (i.t. MTX) reduces the incidence of CNS relapse to 7%-15%. However, increased evidence of CNS delayed toxicity started to be recognized as CT scan abnormalities and neuropsychologic alterations, mainly in children. Two questions were analyzed in the present report: (1) Will further doses of i.t. methotrexate and dexamethasone (i.t. MTX- DMT) decrease the incidence of CNS relapse in patients treated early in remission with cranium irradiation plus i.t. MTX-DMT even more? (2) Is i.t. MTX-DMT given during induction and maintenance equally as effective as cranium irradiation plus i.t. MTX-DMT? A randomized study was designed to answer the first question. Incidence of primary CNS relapse in i.t. MTX-DMT-treated patients with a WBC count less than 50,000 was 11% (15 of 135 patients) and was 11% (17 of 150) in the untreated group. In patients with a WBC count greater than 50,000, it was 16% (6/37) in the treated group and 19% (6/31) in the control group. No difference was observed according to treatment in both prognostic groups. Patients in this study were retrospectively compared with a consecutive protocol in which patients received 3 doses of i.t. MTX-DMT alone during induction plus 3 doses weekly during the first month of remission and every 3 mo thereafter. The incidence of primary CNS leukemia at 60 mo in patients with a WBC count less than 50,000 was 20% in the irradiated group and 32% in the group with i.t. MTX-DMT alone. This difference was not significant. However, the relapse-free survival at 60 mo was 26% and 41%, respectively, (p less than 0.0005). The incidence of primary CNS relapse in patients with a WBC count more than 50,000 at 48 mo was 28% in the irradiated group and 42% in the nonirradiated group. The difference was not significant. The duration of complete remission was similar, remaining at 15% and 16% of patients disease-free at 48 mo, respectively. We conclude that (A) after cranial irradiation plus i.t. MTX-DMT X 5, the use of additional doses of i.t. MTX-DMT is not of further benefit in preventing CNS relapse; (B) the use of i.t. MTX-DMT alone compares similarly with cranial irradiation plus i.t. MTX-DMT in the incidence of CNS relapse; and (C) relapse-free survival and survival in patients with a WBC count less than 50,000 were significantly longer in those without cranial irradiation.

Download Full-text

Efficacy and morbidity of central nervous system "prophylaxis" in childhood acute lymphoblastic leukemia: eight years' experience with cranial irradiation and intrathecal methotrexate

Blood ◽

10.1182/blood.v61.2.297.297 ◽

1983 ◽

Vol 61 (2) ◽

pp. 297-303 ◽

Cited By ~ 69

Author(s):

A Inati ◽

SE Sallan ◽

JR Cassady ◽

S Hitchcock-Bryan ◽

LA Clavell ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Learning Disabilities ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cranial Irradiation ◽

Intrathecal Methotrexate ◽

Cns Prophylaxis ◽

Late Morbidity ◽

Prospective Longitudinal

Abstract Between 1972 and 1979, 214 children with acute lymphoblastic leukemia and no evidence of central nervous system (CNS) disease prior to CNS prophylaxis were treated with 2400 rad cranial irradiation and concurrent intrathecal methotrexate. Only nine children developed CNS leukemia; five of them in the CNS only and four concurrently in the CNS and another site. Major acute effects of CNS prophylaxis were seizures in seven patients (3%). Sixty-nine children who had a minimum follow-up of 4 yr were evaluable for late effects of therapy. Small cataracts, incomplete regrowth of hair, and learning disabilities were noted. The latter occurred in 18% of patients, an incidence similar to that encountered in a normal community of school-age children. However, the incidence of learning disabilities in patients who were under 5 yr of age at the time of diagnosis was much higher, 35%. We conclude that the combination of cranial irradiation and intrathecal methotrexate was highly efficacious. The incidence and severity of neuropsychologic abnormalities, the principal late morbidity of this treatment program, varies among reporting institutions. Prospective longitudinal studies of neuropsychologic function are necessary to better define the incidence of abnormalities. Future programs should attempt to decrease late morbidity, but must also assure equal efficacy and improve overall disease-free survival.

Download Full-text

Central Nervous System Disease in Acute Lymphoblastic Leukemia: Prophylaxis and Treatment

Hematology ◽

10.1182/asheducation-2006.1.142 ◽

2006 ◽

Vol 2006 (1) ◽

pp. 142-146 ◽

Cited By ~ 62

Author(s):

Ching-Hon Pui

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Treatment Options ◽

Central Nervous System Disease ◽

Cranial Irradiation ◽

Childhood All ◽

Excellent Outcome ◽

Cns Relapse

Abstract Improved treatment for acute lymphoblastic leukemia (ALL) has virtually eliminated testicular relapse. However, the control of central nervous system (CNS) leukemia remains a therapeutic challenge in childhood ALL, partly because of the late complications arising from cranial irradiation. In most current pediatric protocols, cranial irradiation (12 to 18 Gy) is given to 5% to 25% of patients—those with T-cell ALL, overt CNS disease (CNS3 status) or high-risk cytogenetics. CNS control is a less urgent concern in adults with ALL, in whom systemic relapse remains the major problem. With current approaches, approximately 2% to 10% of patients can be expected to develop CNS relapse. Children with B-cell precursor ALL who have a late CNS relapse (after an initial remission of 18 months or more) and did not receive cranial irradiation have an excellent outcome after retrieval therapy, with a 5-year event-free survival (EFS) rate approaching that in newly diagnosed patients. Innovative treatment options are needed for children who develop CNS relapses after a short initial remission or after receiving cranial irradiation, and in any adults with CNS leukemia at diagnosis or relapse.

Download Full-text

Efficacy and morbidity of central nervous system "prophylaxis" in childhood acute lymphoblastic leukemia: eight years' experience with cranial irradiation and intrathecal methotrexate

Blood ◽

10.1182/blood.v61.2.297.bloodjournal612297 ◽

1983 ◽

Vol 61 (2) ◽

pp. 297-303

Author(s):

A Inati ◽

SE Sallan ◽

JR Cassady ◽

S Hitchcock-Bryan ◽

LA Clavell ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Learning Disabilities ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cranial Irradiation ◽

Intrathecal Methotrexate ◽

Cns Prophylaxis ◽

Late Morbidity ◽

Prospective Longitudinal

Between 1972 and 1979, 214 children with acute lymphoblastic leukemia and no evidence of central nervous system (CNS) disease prior to CNS prophylaxis were treated with 2400 rad cranial irradiation and concurrent intrathecal methotrexate. Only nine children developed CNS leukemia; five of them in the CNS only and four concurrently in the CNS and another site. Major acute effects of CNS prophylaxis were seizures in seven patients (3%). Sixty-nine children who had a minimum follow-up of 4 yr were evaluable for late effects of therapy. Small cataracts, incomplete regrowth of hair, and learning disabilities were noted. The latter occurred in 18% of patients, an incidence similar to that encountered in a normal community of school-age children. However, the incidence of learning disabilities in patients who were under 5 yr of age at the time of diagnosis was much higher, 35%. We conclude that the combination of cranial irradiation and intrathecal methotrexate was highly efficacious. The incidence and severity of neuropsychologic abnormalities, the principal late morbidity of this treatment program, varies among reporting institutions. Prospective longitudinal studies of neuropsychologic function are necessary to better define the incidence of abnormalities. Future programs should attempt to decrease late morbidity, but must also assure equal efficacy and improve overall disease-free survival.

Download Full-text

Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.3.520 ◽

1993 ◽

Vol 11 (3) ◽

pp. 520-526 ◽

Cited By ~ 110

Author(s):

D G Tubergen ◽

G S Gilchrist ◽

R T O'Brien ◽

P F Coccia ◽

H N Sather ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Survival Rate ◽

Systemic Therapy ◽

Lymphoblastic Leukemia ◽

Intrathecal Methotrexate ◽

Intermediate Risk ◽

Relapse Free Survival ◽

Free Survival ◽

Cancer Group ◽

Cns Relapse

PURPOSE This study (Childrens Cancer Group [CCG]-105) was designed in part to determine in a prospective randomized trial whether intrathecal methotrexate (IT MTX) administered during induction, consolidation, and maintenance could provide protection from CNS relapse equivalent to that provided by cranial radiation (CXRT) in children with acute lymphoblastic leukemia (ALL) and intermediate-risk features. PATIENTS AND METHODS We randomized 1,388 children with intermediate-risk ALL to the two CNS regimens. They received either IT MTX at intervals throughout their course of therapy or CXRT (18 Gy) during consolidation with IT MTX during induction, consolidation, and delayed intensification. Systemic therapy was randomized to one of four treatment regimens derived from a regimen used by CCG in recent studies for this patient population and three more intensive regimens based on the Berlin-Frankfurt-Munster trials. RESULTS Life-table estimates at 7 years show a 93% and 91% CNS relapse-free survival rate for the CXRT and IT MTX groups, respectively. The corresponding event-free survival (EFS) rates are 68% and 64%. The differences are not significant. Patients who received more intensive systemic therapy had a 94% CNS relapse-free survival rate on either CXRT or IT MTX, while patients who received standard systemic therapy had 90% and 80% rates for CXRT and IT MTX, respectively (P < .0001). Patients less than 10 years of age who received CXRT or IT MTX had 72% and 71% EFS rates if they received more intensive systemic therapy. Patients 10 years or older who received CXRT had an improved EFS (61% v 53%) with a more intensive systemic program. This was primarily due to fewer bone marrow relapses (P = .04). CONCLUSIONS IT MTX during induction, consolidation, and maintenance provides protection from CNS relapse in patients with intermediate-risk ALL equivalent to that provided by CXRT if more intensive systemic therapy is given. The CNS relapse rate with either CXRT or IT MTX is in part dependent on the associated systemic therapy. For intermediate-risk patients less than 10 years of age, IT MTX with an intensified systemic regimen provided CNS prophylaxis comparable to that provided by CXRT, whereas older patients had fewer systemic relapses if they received CXRT.

Download Full-text

Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Münster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia Pediatrica.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.10.2497 ◽

1995 ◽

Vol 13 (10) ◽

pp. 2497-2502 ◽

Cited By ~ 66

Author(s):

V Conter ◽

M Aricò ◽

M G Valsecchi ◽

C Rizzari ◽

A M Testi ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cranial Irradiation ◽

Intrathecal Chemotherapy ◽

Intrathecal Methotrexate ◽

Intermediate Risk ◽

Intensive Chemotherapy ◽

Free Survival ◽

Cns Disease ◽

Cns Relapse

PURPOSE To assess the effect of treatment intensification and that of extended intrathecal methotrexate substitution for cranial irradiation in intermediate-risk acute lymphoblastic leukemia (ALL) children treated with a Berlin-Frankfurt-Münster (BFM)-based intensive chemotherapy. PATIENTS Three hundred ninety-six children with non-B-ALL were enrolled onto the Associazione Italiana di Ematologia ed Oncologic Pediatrica (AIEOP) ALL 88 study. Standard risk (SR) included patients with low tumor burden (BFM risk index [RI], < 0.8); intermediate risk (IR) were patients with an RI > or = 0.8 but less than 1.2; and high risk (HR) were those with an RI > or = 1.2 or CNS involvement at diagnosis. The treatment schedule was a modified version of the ALL-BFM 86 study. CNS-directed treatment consisted of high-dose methotrexate (HD-MTX; 5 g/m2 for four courses) plus intrathecal methotrexate (IT-MTX; nine doses); IR patients additionally received extended IT-MTX (nine doses during continuation therapy); cranial irradiation was given only to HR patients. RESULTS Of the 375 (94.7%) children who achieved remission, 1.3% had an adverse event other than relapse. The estimated event-free survival (EFS) at 6 years was 66.6% (SE 2.4) overall; 80.7% (4.5) in the SR patients, 77.5% (3.9) in the IR patients, and 54.5% (3.7) in the HR patients. Relapse occurred in 107 children (27.0%). Isolated CNS relapse occurred in 20 children (5.0%): 5 (6.3%) in the SR group, 1 (0.8%) in the IR group, and 14 (7.1%) in the HR group. The estimated 6-year CNS leukemia-free survival was 94.6% (1.2) overall: 93.5% (2.8) in the SR group, 99.1% (0.9) in the IR group, and 92.3% (2.0) in the HR group. CONCLUSION Cranial irradiation may be omitted safely in IR ALL patients treated with BFM-based intensive chemotherapy when extended intrathecal chemotherapy is given. Because the CNS disease control was less complete in the SR group, these data challenge the effectiveness of HD-MTX for protection from CNS disease and support the protective role of extended intrathecal chemotherapy.

Download Full-text

Pharmacogenetics of the Central Nervous System—Toxicity and Relapse Affecting the CNS in Pediatric Acute Lymphoblastic Leukemia

Cancers ◽

10.3390/cancers13102333 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2333

Author(s):

Judit C. Sági ◽

András Gézsi ◽

Bálint Egyed ◽

Zsuzsanna Jakab ◽

Noémi Benedek ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Acute Lymphoblastic Leukemia ◽

Gene Polymorphisms ◽

Lymphoblastic Leukemia ◽

Toxic Encephalopathy ◽

Inverse Association ◽

Central Nervous System Toxicity ◽

Cns Relapse ◽

The Central Nervous System

Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations’ matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.

Download Full-text

Serial cranial computed-tomography scans in children with leukemia given two different forms of central nervous system therapy.

Journal of Clinical Oncology ◽

10.1200/jco.1983.1.12.793 ◽

1983 ◽

Vol 1 (12) ◽

pp. 793-798 ◽

Cited By ~ 48

Author(s):

J J Ochs ◽

L S Parvey ◽

J N Whitaker ◽

W P Bowman ◽

L Ch'ien ◽

...

Keyword(s):

Computed Tomography ◽

Central Nervous System ◽

Nervous System ◽

Ct Scan ◽

Lymphoblastic Leukemia ◽

Clinical Situation ◽

Cranial Irradiation ◽

Cranial Computed Tomography ◽

Intrathecal Methotrexate ◽

Central Nervous System Toxicity

Cranial computed tomography (CT) was used to estimate the frequency and permanence of brain abnormalities in 108 consecutive children with acute lymphoblastic leukemia (ALL). Fifty-five patients received cranial irradiation (1,800 rad) with intrathecal methotrexate (RT group) and 53 patients received intravenous and intrathecal methotrexate without irradiation (IVIT group). Continuation treatment included sequential drug pairs for the RT group and periodic IVIT methotrexate for the other group. After 12 to 24 months of serial evaluation, five (9%) of the 55 patients in the RT group have had CT scan abnormalities, compared to 10 (19%) of 52 in the IVIT group (p = 0.171). Fourteen of the 15 patients with CT scan abnormalities had focal or diffuse white-matter hypodensity; these have reverted to normal in most cases, reflecting a dynamic process. While such CT findings are of concern and may be an early indicator of central nervous system toxicity, this remains to be proven. Therapy should not be altered on the basis of abnormal CT scans alone but in the context of the entire clinical situation.

Download Full-text